Alkylating agents are an important class of anticancer drugs, which express their cytotoxic and antitumour effects by forming adducts with cellular DNA. The bisbenzimidazole moiety itself has been reported in the literature as an efficient DNA minor groove binding agent, and a number of compounds of this general structure have been reported to have DNA binding and cytotoxic properties. In particular, the compound pibenzimol (Hoechst 33258), which binds to regions of the minor groove rich in adenine and thymine bases, and its analogues, have been intensively investigated. See for example:
Loewe, V. H. and Urbanietz, I. "Basisch substituierte 2,6-Bis-benzimidazolederivate, eine neue chemotherapeutisch aktive Korperklass" Arz.-Forschung, 1974 24 1927-1933. PA0 Bathini, Y. and Lown, J. W. "Convenient routes to substituted benzimidazoles and imdazolo[4,5-b]pyridines using nitrobenzene as oxidant" Synth. Comm., 1990 20 955-963. PA0 Beerman, T. A., McHugh, M. M., Sigmund, R., Lown, J. W., Rao, K. E. and Bathini, Y. "Effects of analogs of the DNA minor groove binder Hoechst 33258 on topoisomerase II and I mediated activities" Biochim. Biophys. Acta., 1992 1131 53-61. PA0 Kelly, D. P., Bateman, S. A., Martin, R. F., Reum, M. E., Rose, M. and Whittaker, A. R. D. "DNA binding compounds. V. Synthesis and characterisation of boron-containing bisbenzimidazoles related to the DNA minor groove binder Hoechst 33258" Aus. J. Chem., 1994 47 247-262. PA0 Wang, H., Gupta, R. and Lown, J. W. "Synthesis, DNA binding, sequence preference and biological evaluation of minor groove selective N1-alkoxyalkyl bisbenzimidazoles" Anti-Cancer Drug Design, 1994 9 153-180.
A recent publication [Lee, M., Walker, C. D., Eckert, J. M., Bowers, S. K., Montague, D., McAdams, S. and Hartley, J. A., "DNA sequence selective alkylation and cytotoxicity of monoheterocyclic analogues of Hoechst 33258", Med. Chem. Res., 1993 3 79-86] describes three monobenzimidazole mustard compounds. Subsequent to the priority date of this application, a further publication [Gupta, R., Wang, H., Huang, L. And Lown, J. W. "Design, synthesis, DNA sequence preferential alkylation and biological evaluation of N-mustard derivatives of Hoechst 33258 analogues", Anti-Cancer Drug Design, 1995 10 25-41] has described four mixed benzimidazole/benzoxazole mustard analogues of Hoechst 33258.
We have now developed a novel class of bisbenzimidazole compounds which have not only the ability to bind to DNA in the minor groove, but also to alkylate DNA. These compounds show good anti-tumour activity both in vitro and in vivo.